The MUC1 heterodimeric oncoprotein is aberrantly expressed at high levels in over 90% of human breast cancers. The MUC1 N-terminal subunit (MUC1-N) is a mucin-type glycoprotein that disrupts cell-cell and cell-extracellular matrix interactions. The MUC1 C-terminal subunit (MUC1-C) binds to the Wnt pathway effector, ?-catenin, and functions as a transmembrane receptor. Our work has also demonstrated that MUC1 interacts with EGFR, ErbB2, c-Src and GSK32, indicating that MUC1 integrates the ErbB receptor and Wnt signaling pathways. Other studies supported by this grant have demonstrated that MUC1-C is targeted (i) to the nucleus where it functions in the regulation of gene transcription, and (ii) to mitochondria where it attenuates permeabilization of the mitochondrial outer membrane. These findings have provided new insights into the potential role of MUC1 in the development of human breast carcinomas. What is needed now, at least in part, is a more precise understanding of the biologic significance of MUC1 in breast cancer. Our hypothesis is that MUC1 functions physiologically in the protection of normal mammary epithelial cells and that the MUC1 gene is activated by the heregulin (HRG)-induced stress response. Our hypothesis is also that the MUC1-C subunit transduces signals from the cell membrane to the nucleus and mitochondria that confer a growth and survival response to stress. The overexpression of MUC1 as found in most human breast cancers is therefore proposed as a mechanism by which physiologic MUC1 functions have been exploited in the aberrant regulation of tumor growth and survival. The Specific Aims are: 1) To define the role of Muc1 in mammary gland tumorigenesis;2) To elucidate the mechanisms responsible for upregulation of MUC1 expression in nontransformed and malignant mammary epithelial cells;3) To determine the functional significance of the interaction between MUC1 and galectin-3 on cell surface signaling;4) To define the effects of nuclear MUC1-C on occupancy and activation of Wnt target genes;and 5) To assess the role of MUC1-C in restraining apoptosis in the cytosol and at the mitochondrial outer membrane. PUBLIC HEALTH RELEVANCE: Breast cancer is one of the leading causes of death among women. The MUC1 protein contributes to the development of breast cancer in experimental models and is expressed at high levels in over 90% of human breast tumors. Our proposed research on MUC1 should provide a better understanding of the causes of breast cancer and potentially new opportunities for treatment.